The long term goal of this project is to develop a new generation of immunotherapeutic drugs for the treatment of immune diseases such as graft-versus-host disease (GVHD) that will be more specific and advantageous than the currently marketed non-specific general immunosuppressive drugs such as Cyclosporin and FK506 or the T cell-depletion medical procedure. The mechanistic basis for this project is that small surface regions of CD8 are critical functional epitopes mediating major histocompatibility complex (MHC)class I interaction and T cell function, and therefore small molecules targeting these epitopes can block CD8-MHC class I interaction and be used as effective immunotherapeutic drugs. Extensive preliminary studies have shown strong supporting evidence and data for our drug discovery approach and led to the discovery of a peptide lead compound, termed 1109 peptide, derived from the CD8 DE loop that is highly conserved between humans and mice and important for CD8 function. We have shown that 1109 peptide significantly inhibited CD8 dependent immunological activity in vitro and in vivo. To further develop 1109 peptide into more potent and stable analogs for future clinical application, we have developed various peptidomimetic modification strategies to increase the activity and proteolytic stability of the peptide. Here in this proposal we plan to apply these peptidomimetic modification approaches to modify 1109 lead peptide in order to generate highly potent and stable analogs as new drugs for the treatment of CD8+ T cell mediated diseases such as GVHD.